1. Field of the Invention
The present invention is directed towards new phosphonamide compounds and methods of forming those compounds via ring-closing metathesis reactions carried out in the presence of a ring-closing catalyst (e.g., a Grubbs catalyst), or via reacting a template structure with a phosphorus (III) compound to yield complex phosphonamides. The compounds have a number of uses including as inhibitors of enzymes such as HIV proteases.
2. Description of the Prior Art
Small peptides are excellent starting points for drug design because they have the potential to overcome the pharmnacokinetic shortcomings of larger peptides, yet retain the desirable quality of molecular recognition. A number of dipeptides are currently being developed as novel pharmaceutical agents (see e.g., Blackburn et al., Bioorg. Med. Chem. Lett., 7:823-26 (1997); Schullek et al., Anal. Biochem., 246:20-29 (1997), each incorporated by reference herein). Unfortunately, even small peptides suffer from proteolytic instability which limits their use as drug candidates.
Peptide mimics have been developed which utilize the urea moiety as a non-hydrolyzable linker and/or a hydrogen bond acceptor. Further modifications to cyclic ureas have led to the generation of a new sub-class of biologically active compounds. A number of cyclic HIV protease inhibitors have been developed that incorporate ureas, sulfamides, and other urea surrogates as the central linchpin. In these cases, it has been shown that the H-bonding urea moieties may serve to replace the water molecule exclusive to the active site of HIV protease. Ring-closing metathesis (RCM) reactions have become a highly effective strategy for the construction of a number of important heterocyclic compounds (see e.g., Fu et al., J. Am. Chem. Soc., 115:9856 (1993), incorporated by reference herein) and constrained peptides (see e.g., Miller et al., J. Am. Chem. Soc., 117:5855-5856 (1995); Miller et al., J. Am. Chem. Soc., 118:9606-9614 (1996); Blackwell et al., Angew. Chem., Int. Ed., 37:3281-3284 (1998), each incorporated by reference herein).
Since its discovery as the causative agent of AIDS, considerable effort has been placed on understanding the biomolecular replicative process of the human immunodeficiency virus (HIV), with primary focus being placed on the inhibition of a key virally encoded protease enzyme of the pol gene. Many synthetic approaches to the inhibition of HIV protease are based on the synthesis of peptidomimetics which replace a key scissile amide bond by a non-hydrolyzable transition state isostere. This strategy has been employed to synthesize a number of novel nonpeptidal HIV protease inhibitors. Among the more effective peptidomimetics, the synthesis of cyclic ureas (see e.g., Lucca et al., Drugs of the Future, 23:987 (1998)), cyclic sulfamides (see e.g., Jadhav et al., Tetrahedron Lett., 36:6383 (1995)), hydroxyethylene/hydroxyethylamine isosteres (see e.g., Thomas et al., Biorg. Med. Chem. Lett., 4:2759 (1994)) have been reported.
Finally, phosphorus-containing compounds have gained considerable attention due to their diverse biological and chemical profiles. A number of P-heterocycles have shown potent biological activity and have thus become attractive targets as rationally designed small molecules (see e.g., Zon, Progr. Med. Che., 19:205-46 (1982); Nachev, Bull. Chem. Soc. Jpn., 61:3705-9 (1988); and Stec, J. Organophosphorus Chem., 13:145-74 (1982), each incorporated by reference herein).
The present invention is broadly concerned with new phosphonamide compounds and methods of forming such compounds.
In more detail, the preferred compounds are represented by a formula selected from the group consisting of 
wherein:
each X is individually selected from the group consisting of oxygen, xe2x80x94NH, and xe2x80x94NOR;
each R is individually selected from the group consisting of hydrogen, branched and unbranched alkyl groups (preferably C1-C18, more preferably C1-C8), branched and unbranched alkenyl groups (preferably C2-C18, more preferably C2-C8), branched and unbranched alkynyl groups (preferably C2-C18, more preferably C2-C8), allyl groups, acyl groups (preferably C1-C18, more preferably C1-C8), aryl groups (preferably C6-C12), 2-15 mer peptides, and benzyl groups; and
each R1 is individually selected from the group consisting of hydrogen, amino acid side chains, and 2-15 mer peptides.
Preferably at least one R1 group comprises an amino acid side chain selected from the group consisting of 
wherein each R2 is individually selected from the group consisting of hydrogen, branched and unbranched alkyl groups (preferably C1-C18, more preferably C1-C8), branched and unbranched alkenyl groups (preferably C2-C18, more preferably C2-C8), branched and unbranched alkynyl groups (preferably C2-C18, more preferably C2-C8), allyl groups, aryl groups (preferably C6-C12), acyl groups (preferably C1-C18, more preferably C1-C8), and benzyl groups.
In a preferred embodiment, the inventive compounds comprise a formula selected from the group consisting of 
Some of the inventive compounds are formed by reacting a template phosphonamide compound which comprises an opened-ring structure (i.e., a partially-formed ring comprising at least half, but not all of the sides necessary to form a cyclic compound) with a ring-closing catalyst to yield the closed-ring phosphonamide compound. Preferred ring-closing catalysts are Grubbs catalysts (see e.g., U.S. Pat. Nos. 6,048,993, 5,917,071, 5,750,815, 5,710,298, 5,342,909, and 5,312,940, each incorporated by reference herein) as well as those disclosed by the following references, each also incorporated by reference herein: Matthias, Org. Ltrs., 1(6):953-56 (1999); Schrock, Macromolecules, 29(19):6114-25 (1996); Zhu et al., J. Amer. Chem. Soc., 121(36):8251-59 (1999); Alexander et al., J. Amer. Chem. Soc., 120(16):4041-42 (1998); and Kingsbury et al., J. Amer. Chem. Soc., 121(4):791-99 (1999).
Particularly preferred Grubbs catalysts are those selected from the group consisting of 
Preferred template opened-ringed structures comprise an allylated phosphonamide, with particularly preferred template structures being those selected from the group consisting of 
wherein:
each X is individually selected from the group consisting of oxygen, xe2x80x94NH, and xe2x80x94NOR;
each R is individually selected from the group consisting of hydrogen, branched and unbranched alkyl groups (preferably C1-C18, more preferably C1-C8), branched and unbranched alkenyl groups (preferably C2-C18, more preferably C2-C8), branched and unbranched alkynyl groups (preferably C2-C18, more preferably C2-C8), allyl groups, acyl groups (preferably C1-C18, more preferably C1-C8), aryl groups (preferably C6-C12), 2-15 mer peptides, and benzyl groups; and
each R1 is individually selected from the group consisting of hydrogen, amino acid side chains, and 2-15 mer peptides.
Preferred closed-ring phosphonamide compounds formed by this inventive method are those selected from the group consisting of 
wherein:
each X is individually selected from the group consisting of oxygen, xe2x80x94NH, and xe2x80x94NOR;
each R is individually selected from the group consisting of hydrogen, branched and unbranched alkyl groups (preferably C1-C18, more preferably C1-C8),. branched and unbranched alkenyl groups (preferably C2-C18, more preferably C2-C8), branched and unbranched alkynyl groups (preferably C2-C18, more preferably C2-C8), allyl groups, acyl groups (preferably C1-C18, more preferably C1-C8), aryl groups (,preferably C6-C12), 2-15 mer peptides, and benzyl groups; and
each R1 is individually selected from the group consisting of hydrogen, amino acid side chains, and 2-15 mer peptides.
Preferably the reacting step is carried out at a temperature of from about 15-80xc2x0 C., and more preferably from about 30-55xc2x0 C. Furthermore, the reacting step should be carried out in a solvent system comprising a solvent selected from the group consisting of toluene, benzene, chlorobenzene, dichlorobenzene, methylene chloride, dimethoxyethane (DME), and mixtures thereof. Preparing the phosphonamide compounds according to the inventive methods should result in a yield of those compounds of at least about 80%, and preferably at least about 95%, wherein the theoretical yield is taken as 100%.
In another embodiment, the sterically demanding inventive compounds can be prepared with relative ease by providing a template compound comprising two secondary amines bonded to an alkyl chain with the nitrogen atoms of the respective amines being separated by at least two carbon atoms, and preferably at least four carbon atoms, on the alkyl chain. The template compound is then reacted with a phosphorus (III) compound under conditions to cause the phosphorus atom thereof to bond with each of the amine nitrogen atoms, thus forming a cyclic phosphonamide.
Preferred phosphorus (III) compounds have the formula R3PY2, wherein:
R3 is selected from the group consisting of hydrogen, branched and unbranched alkyl groups (preferably C1-C18, more preferably C1-C8), branched and unbranched alkenyl groups (preferably C2-C18, more preferably C2-C8), branched and unbranched alkynyl groups (preferably C2-C18, more preferably C2-C8), allyl groups, acyl groups (preferably C1-C18, more preferably C1-C8), aryl groups (preferably C6-C12), and benzyl groups; and
each Y is individually selected from the group consisting of the halogens.
Even more preferably, the phosphorus (III) compound comprises the formula PhPCl2.
Preferred templates have a general formula selected from the group consisting of 
wherein:
each X is individually selected from the group consisting of oxygen, xe2x80x94NH, and xe2x80x94NOR;
each R is individually selected from the group consisting of 2-15 mer peptides, hydrogen, branched and unbranched alkyl groups (preferably C1-C18, more preferably C1-C8), branched and unbranched alkenyl groups (preferably C2-C18, more preferably C2-C8), branched and unbranched alkynyl groups (preferably C2-C18, more preferably C2-C8), allyl groups, acyl groups (preferably C1-C18, more preferably C1-C8), aryl groups (preferably C6-C12), and benzyl groups; and
each R1 is individually selected from the group consisting of hydrogen, amino acid side chains, and 2-15 mer peptides.
Preferred cyclic phosphonamides formed according to this method include those selected from the group consisting of 
wherein:
each X is individually selected from the group consisting of oxygen, xe2x80x94NH, and xe2x80x94NOR;
each R is individually selected from the group consisting of hydrogen, branched and unbranched alkyl groups (preferably C1-C18, more preferably C1-C8), branched and unbranched alkenyl groups (preferably C2-C18, more preferably C2-C8), branched and unbranched alkynyl groups (preferably C2-C18, more preferably C2-C8), allyl groups, acyl groups (preferably C1-C18, more preferably C1-C8), aryl groups (preferably C6-C12), 2-15 mer peptides, and benzyl groups; and
each R1 is individually selected from the group consisting of hydrogen, amino acid side chains, and 2-15 mer peptides.
Preferably the reacting step is carried out at a temperature of from about xe2x88x9210-25xc2x0 C., and more preferably from about xe2x88x9210-0xc2x0 C. Furthermore, the reacting step should be carried out in a solvent system comprising a solvent selected from the group consisting of methylene chloride, acetonitrile, diethyl ether, and mixtures thereof. Preparing the phosphonamide compounds according to this embodiment of the inventive methods should result in a yield of those compounds of at least about 80%, and preferably at least about 95%, wherein the theoretical yield is taken as 100%.
It will be appreciated that the inventive methods allow for the synthesis of a wide array of both symmetric and unsymmetric cyclic phosphonamide compounds. Furthermore, the inventive methods allow for preparation of, or selection of, templates having particular functional groups bonded thereto which are then readily formed into the desired phosphonamide in a controlled and repeatable manner. Because the method can be adapted to form phosphonamide compounds comprising one or more amino acid side chains or peptides bonded thereto, the inventive compounds can be used to inhibit enzymes such as HIV protease.